Prenatal Genetic Diagnosis by Genomic Sequencing

Overview

This study is evaluating the impact of prenatal sequencing on the management of fetuses with ultrasound abnormalities. The hypothesis is that a significant subset of fetal abnormalities have a genetic cause that can be identified by sequencing and that prenatal knowledge of this information will improve prenatal care, reduce unnecessary diagnostic testing, reduce the cost of care, and improve the quality of life for both the child and the family.

Full Title of Study: “Prenatal Genetic Diagnosis by Genomic Sequencing: A Prospective Evaluation”

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: August 31, 2023

Detailed Description

Whole exome and whole genome sequencing (WGS) have expanded the ability to determine the genetic etiology of previously undiagnosed disorders. This study is a multicenter prospective cohort study to evaluate the emerging technology of sequencing for the management of fetuses with structural anomalies. The hypothesis is that a significant subset of fetal structural anomalies has a genetic etiology identifiable by sequencing and that prenatal knowledge of this information will improve perinatal care, reduce unnecessary diagnostic testing, reduce the cost of care, and improve quality of life for both the child and the family. The aims of this study are to investigate these multiple aspects of prenatal sequencing in a single study with an innovative integrated prospective design, which will permit a robust evaluation of the benefits and risks of delivering diagnostic and prognostic genetic testing results in a prenatal setting. The study will determine, in a sequential population of pregnancies with selected fetal structural anomalies and a negative or non-causal chromosomal microarray (CMA), the frequency of pathogenic, likely pathogenic, and uncertain genomic variants identifiable by sequencing. To determine the impact of this information on clinical care, a control population of unsequenced pregnancies with similar structural anomalies will be prospectively recruited and the infants from both cohorts will be followed up to 1 year of age. This study component will evaluate differences in healthcare management and cost through discharge from hospital post-delivery, and perinatal and infant outcomes through 1 year of life. The educational, counseling and psychosocial impact of sequencing results during the prenatal period, in the nursery and through 1 year of life also will be evaluated. Since the analytical and clinical tools needed for the full translation of sequencing into care are still developing, optimization of bioinformatic tools to improve identification of pathogenic and likely pathogenic mutations associated with prenatal phenotypes of established disease genes will be investigated, as well as identification of new genes associated with presently undiagnosed fetal/neonatal phenotypes. This study will provide an in-depth evaluation of the prenatal diagnostic value of sequencing prior to its responsible introduction into practice and will provide independent data to guide its translation.

Interventions

  • Diagnostic Test: Prenatal Genomic Sequencing
    • Whole genome sequencing (which initially will be masked and reported as exome only)

Arms, Groups and Cohorts

  • Prenatally Sequenced Group
    • 750 trios with fetal structural anomalies who receive prenatal sequencing from the study
  • No Prenatal Sequencing (Unsequenced) Group
    • 350 trios with fetal structural anomalies who do not have prenatal sequencing

Clinical Trial Outcome Measures

Primary Measures

  • Reportable Variants
    • Time Frame: Approximately 4.5 years
    • Reportable variants (defined as either Pathogenic, likely pathogenic, or VUS) identified by sequencing and deemed reportable by the Variant Adjudication Committee.
  • Healthcare Costs
    • Time Frame: Approximately 4.5 years
    • Healthcare costs from time of diagnosis of anomaly to infant discharge between sequenced and unsequenced groups.

Secondary Measures

  • Perinatal Outcomes by Medical Record Review
    • Time Frame: Approximately 4.5 years
    • Perinatal outcomes will be compared and outcomes will be measured by: gestational age at delivery, major morbidities including length of ventilator support, sepsis, need for pressor support, need for ECMO, metabolic abnormalities (e.g., acidosis, elevated uric acid, hypo-/hyperglycemia), intraventricular hemorrhage/periventricular leukomalacia, encephalopathy, and seizure.
  • Death
    • Time Frame: Approximately 4.5 years
    • Neonatal/infant death at time of discharge and at 12 months of age.
  • NICU Stay Duration
    • Time Frame: Approximately 4.5 years
    • Length of initial NICU stay and number of days spent in the hospital between initial discharge and 12 months of age.
  • Length in centimeters
    • Time Frame: Approximately 4.5 years
    • Infant length at 12 months of age.
  • Weight in kilograms
    • Time Frame: Approximately 4.5 years
    • Infant weight at 12 months of age.
  • Development by Ages and Stages Questionnaire
    • Time Frame: Approximately 4.5 years
    • Developmental outcomes defined by the following parameters: communication, gross motor, fine motor, problem solving and personal-social, at 12 months of age using ASQ-3. Lower scores are associated with developmental delay. Cutoffs for 12 month exam are: Communication 15.64, Gross Motor 21.49, Fine Motor 34.5, Problem Solving 27.32, Personal-Social 21.73
  • Anxiety by self-report questionnaire
    • Time Frame: Approximately 4.5 years
    • Anxiety following result disclosure (or 8 weeks post enrollment for the unsequenced group), neonatal discharge and 12 months postpartum.
  • Depression/Anxiety by self-report questionnaire
    • Time Frame: Approximately 4.5 years
    • Depression following result disclosure (or 8 weeks post enrollment for the unsequenced group), neonatal discharge and 12 months postpartum.
  • Quality of Life by self-report questionnaire
    • Time Frame: Approximately 4.5 years
    • Quality of life for the patient and family at 12 months postpartum.
  • QALY, measured in cost per year
    • Time Frame: Approximately 4.5 years
    • Incremental cost per Quality Adjusted Life Year (QALY).
  • Phenotypic Expansion – identification of new phenotypes associated with disease- Sequenced Group ONLY
    • Time Frame: Approximately 4.5 years
    • Apparent prenatal phenotypic expansion from currently defined pediatric phenotypes.
  • VUS frequency and outcome- Sequenced Group ONLY
    • Time Frame: Approximately 4.5 years
    • Variants of uncertain significance (VUS) that have not yet been associated with this disease phenotype.
  • GUS frequency and outcome- Sequenced Group ONLY
    • Time Frame: Approximately 4.5 years
    • VUS subclassified as compelling variants in novel genes that are not yet disease associated (genes of uncertain clinical significance; GUS).
  • Digital WES – comparison of coding and non-coding results – Sequenced Group ONLY
    • Time Frame: Approximately 4.5 years
    • Pathogenic, likely pathogenic and VUS variants identified by sequencing (coding and non-coding regions) compared with coding regions only (digital WES).
  • Proband Only Versus Trio – comparison of results between trio and proband only – Sequenced Group ONLY
    • Time Frame: Approximately 4.5 years
    • Pathogenic, likely pathogenic and VUS variants identified by analysis of a proband alone compared to a proband-parent trio.
  • Change in Management (healthcare) as Determined by NICU physician and record review – Sequenced Group ONLY
    • Time Frame: Approximately 4.5 years
    • Change in management decisions attributable to genomic results defined as changes to the patient’s treatment plan or changes to the counseling of the patient/family regarding the immediate or long-term medical management.
  • Parental Understanding by self-report questionnaire – Sequenced Group ONLY
    • Time Frame: Approximately 4.5 years
    • Accuracy of parental understanding of genetic test results.
  • Parental Support Needs – by self-report questionnaire – Sequenced Group ONLY
    • Time Frame: Approximately 4.5 years
    • Educational/counseling and social support needs of the mother and father.
  • Classification Over Time (Change in the sequencing result over time) – Sequenced Group ONLY
    • Time Frame: Approximately 4.5 years
    • Changes in classification of sequencing variants over time.
  • Turnaround Time – Sequenced Group ONLY
    • Time Frame: Approximately 4.5 years
    • Turnaround time of sequencing components and how it changes over time.

Participating in This Clinical Trial

Inclusion Criteria

Prenatal sequencing group 1. Fetus identified by ultrasound and/or MRI with at least one of the following: 1. One or more major structural anomalies (Appendix A) 2. A nuchal translucency measurement of ≥ 3.5 mm 3. A fetus less than 24 weeks 0 days gestation with normal anatomy and sonographically estimated fetal weight <5th %ile without maternal hypertension, type I diabetes, or other maternal disorders known to alter fetal growth. 2. Negative prenatal CMA (or those with CMA findings not related to the ultrasound finding) 3. Singleton gestation 4. Gestational age less than 36 weeks, 0 days to allow for availability of sequencing results before delivery Unsequenced Group 1. Fetus identified by ultrasound and/or MRI with at least one of the following: 1. One or more major structural anomalies (Appendix A) 2. A nuchal translucency measurement of ≥ 3.5 mm 3. A fetus less than 24 weeks 0 days gestation with normal anatomy and sonographically estimated fetal weight <5th %ile without maternal hypertension, type I diabetes, or other maternal disorders known to alter fetal growth 2. Negative prenatal or postnatal CMA (or those with CMA findings not related to the ultrasound finding) 3. Declined prenatal sequencing 4. Singleton gestation Exclusion Criteria:

Prenatal Sequencing Group 1. Prenatal sequencing or planned prenatal sequencing performed outside of the study, including gene panels 2. Maternal or paternal age less than 18 years old 3. Proven infectious or teratogenic cause of fetal anomaly 4. Planned termination of the pregnancy 5. Unavailable blood or saliva samples from both biologic parents prior to sequencing 6. Parental unwillingness to participate in 1 year postnatal follow-up 7. Language barrier (non-English or Spanish speaking) 8. Delivery planned at a site other than one of the study centers or associated hospitals 9. Previous consent to the unsequenced prenatal group or enrollment in a previous pregnancy Unsequenced Group 1. Maternal or paternal age less than 18 years old 2. Proven infectious or teratogenic cause of fetal anomaly 3. Positive prenatal NIPT screening for trisomy 21,18 or 13. Positive 22q11.2 prenatal NIPT testing with consistent ultrasound findings is also an exclusion. 4. Planned termination of the pregnancy 5. Parental unwillingness to participate in 1 year postnatal follow-up 6. Language barrier (non-English or Spanish speaking) 7. Delivery planned at a site other than one of the study centers or associated hospitals

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Columbia University
  • Collaborator
    • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
  • Provider of Information About this Clinical Study
    • Principal Investigator: Ronald J Wapner, MD, Director, Reproductive Genetics, Vice Chair of Research, Department of OBGYN – Columbia University
  • Overall Official(s)
    • Ronald Wapner, MD, Principal Investigator, Columbia University
  • Overall Contact(s)
    • Melissa Stosic, MS, 646-565-9501, ms3342@cumc.columbia.edu

Clinical trials entries are delivered from the US National Institutes of Health and are not reviewed separately by this site. Please see the identifier information above for retrieving further details from the government database.

At TrialBulletin.com, we keep tabs on over 200,000 clinical trials in the US and abroad, using medical data supplied directly by the US National Institutes of Health. Please see the About and Contact page for details.